This proposal is designed to build upon the epidemiologic and molecular genetic findings from our research on tobacco-related epithelial cancers. Tobacco exposure is an established risk factor for renal cell carcinoma (RCC). However, there are limited data on susceptibility markers and epidemiologic profiles for RCC We therefore propose to use a molecular epidemiologic approach in a case-control study to identify interindividual differences in inherited genetic instability, focusing on assessing DNA damage/repair, telomere length, and telomerase activity as predictors of RCC risk. In addition, deletions involving 3p are the most common genetic alterations in RCC, we will also study 3p latent genetic instability. We will accrue 300 patients with RCC, who have not received chemotherapy or radiotherapy, identified from two hospitals in the Houston, Texas metropolitan area. We will also recruit 300 controls identified from population-based random digit dialing in the Houston metropolitan area. The controls will be matched to the patients by sex, age (+/- 5 years), and ethnicity. Comprehensive epidemiologic prof'des will be constructed for these patients and controls. Specific goals of this project are: 1): To assess two mutagen sensitivity or DNA repair assays performed in parallel and measured by Komet 4.0 image system in patients and controls. One assay quantifies gamma-radiation-induced lymphocytic tail moment reflecting base excision repair (BER) and double strand break (DSB)/recombination repair; the other assay quantifies benzo[a]pyrene diol-epoxide (BPDE)-induced lymphocytic tail moment reflecting nucleotide excision repair (NER). Our hypothesis is that subjects who show increased y-radiation and BPDE sensitivity are at greater risk for RCC than are those who do not show these sensitivities. 2): To determine the telomere length in peripheral blood lymphocytes (PBLs) at baseline in patients and controls. Our hypothesis is that individuals susceptible to RCC will have shorter telomere length at baseline compared with normal individuals and that telomere length at baseline might be inversely correlated with y-radiation sensitivity. 3): To determine the levels of telomerase activity in PBLs at baseline and after 7- radiation treated of patients and controls. Our hypothesis is that upon exposure to y-radiation, individuals susceptible to RCC will have higher telomerase activity compared with healthy individuals. 4): To determine the frequencies of BPDE-induced chromosome aberrations on 3p12.3, 3p14.2, 3p21.3, and 3p25.2 in PBLs of patients and controls. 3p is the most frequently reported abnormal region in RCC. Our hypothesis is that cases exhibit higher frequencies of BPDE-induced 3p aberrations in PBLs than do controls. These chromosomal loci may reflect genetic susceptibility of specific loci to BPDE and that individuals with aberrations at these loci are at increased risk for RCC. We also plan to conduct a substudy as a secondary aim to perform the loss of heterozygosite (LOH) analysis on 3p on the corresponding tumor tissue from Specific Aim 4. We hypothesize that there will be concordance in the severity of site-specific chromosomal lesions in target and surrogate tissues. This study will further the understanding of the genetic events leading to the development of RCC; explore the genetic basis for genetic instability and how it affects cancer risk; and eventually provide a means of identifying a subgroup who are most likely to develop RCC. Such individuals may then be targeted for intervention programs such as chemoprevention or dietary modification.